Publications
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Bardan, Imane; Sundbakk, Lene Maria; Sexton, Joseph; Kvien, Tore Kristian Aaserud; Molberg, Øyvind & Kristianslund, Eirik
[Show all 8 contributors for this article]
(2026).
Comorbidity and mortality in adults with juvenile idiopathic arthritis: a nationwide Norwegian register-based matched cohort study.
Rheumatology.
ISSN 1462-0324.
doi:
10.1093/rheumatology/keag507.
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Abstract Objectives This population-based study assesses comorbidities, autoimmune conditions and all-cause mortality in (1) adults with juvenile idiopathic arthritis (JIA) against general population comparators and (2) adults with JIA with versus without recent disease-modifying anti-rheumatic drug (DMARD) exposure. Methods We included adults who, between 2009-2024, had ≥ 2 specialist health contacts with a JIA-specific ICD-10 code in the mandatory Norwegian Patient Registry (NPR). Each case was matched randomly, by age, gender and county of residence, to 10 general population comparators at the time of receiving the 2nd JIA diagnosis in adulthood. We compared 5-year retrospective comorbidity prevalences in descriptive analyses and prospective all-cause mortality in (1) adults with JIA versus comparators and (2) adult JIA with versus without recent DMARD exposure. Results Adults with JIA (N = 2932) had higher prevalence than comparators (N = 29 097) of ischemic heart disease excluding myocardial infarction (JIA vs. comparators (%): 1.0 vs. 0.6), hypertension (3.6 vs. 1.4), chronic kidney disease (0.5 vs. 0.2), type 1 diabetes (1.7 vs. 0.7), celiac disease (1.4 vs. 0.7), autoimmune thyroiditis (0.3 vs. 0.1) and autoimmune alopecia (0.4 vs. 0.1). Prospective all-cause mortality was higher in JIA than comparators (mortality rate 2.4 vs. 1.8 per 1000 person-years). In adult JIA, prevalences of comorbidities and autoimmune conditions as well as all-cause mortality, was similar in those with and without recent DMARD exposure. Conclusion In this study we found an increased 5-year retrospective prevalence of several comorbidities and increased all-cause mortality in adults with JIA compared to population controls.
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Tengesdal, Stig; Molberg, Øyvind; Holme, Øyvind; Ghiasvand, Reza; Gran, Jan Tore & Myklebust, Geirmund
(2026).
Lifetime risk of malignancy in polymyalgia rheumatica: a population-based matched cohort study from southern Norway.
Rheumatology.
ISSN 1462-0324.
65(6).
doi:
10.1093/rheumatology/keag297.
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Vikse, Jens; Lanzillotta, Marco; Goni, Elisabetta; Fevang, Bjørg Tilde Svanes; Midtvedt, Øyvind & Mahajne, Jasmin
[Show all 18 contributors for this article]
(2026).
Rituximab limits glucocorticoid use in IgG4-related disease: Real-world evidence from a large European cohort.
European journal of internal medicine.
ISSN 0953-6205.
doi:
10.1016/j.ejim.2026.106832.
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Objectives
While glucocorticoids have been considered the standard of care for IgG4-related disease (IgG4-RD), rituximab is increasingly used off-label. We aimed to evaluate the glucocorticoid-sparing ability of rituximab using real-world data.
Methods
This was an observational multicenter study including adult IgG4-RD patients from three European referral centers treated with glucocorticoids or rituximab (± glucocorticoids). The primary endpoint was no glucocorticoid use at 6 months. Secondary endpoints included treatment response (≥ 2-point decline in responder index (RI)), remission (RI = 0) and flare. Key safety measures included infections requiring hospitalization, and death. We applied logistic regression adjusted for potential confounders.
Findings
We included 167 patients, 115 (68.9 %) in the rituximab and 52 (31.1 %) in the glucocorticoid group. At baseline, the rituximab group was younger, had longer disease duration, more often relapsing disease and higher RI score than the glucocorticoid group. Despite these indicators of more severe disease, a higher proportion of patients in the rituximab group were free from glucocorticoids by 6 months (OR 3.62, 95 % CI 1.06-12.43, p = 0.040). The median cumulative prednisolone dose at 12 months was 1640.0 mg (IQR 150.0-2578.8) for the rituximab group, and 2950.0 mg (IQR 2302.0-4120.0) for the glucocorticoid group (p < 0.001). The secondary endpoints were similar between groups.
Interpretation
While the rituximab-treated patients in this study had more severe IgG4-RD than the glucocorticoid-treated comparators, treatment with rituximab was associated with similar effectiveness endpoints, while significantly reducing glucocorticoid use.
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Goni, Elisabetta; Vikse, Jens; Lanzillotta, Marco; Fevang, Bjørg Tilde Svanes; Midtvedt, Øyvind & Mahajne, Jasmin
[Show all 17 contributors for this article]
(2026).
Effectiveness and safety of rituximab across the four phenotypes of IgG4-related disease: a European multi-center cohort study.
European journal of internal medicine.
ISSN 0953-6205.
143.
doi:
10.1016/j.ejim.2025.106459.
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Objective
Assess relative effectiveness and safety of rituximab (RTX) across the four phenotypes of IgG4-related disease (IgG4-RD).
Methods
We included phenotypically defined adult IgG4-RD patients treated with RTX +/- glucocorticoids (GC) who had evaluable data at 6 months on the composite primary outcome, which included: (i) treatment response (>= 2-point decline in responder index (RI)); (ii) absence of flare; and (iii) GC dose <= 7.5 mg prednisolone. Additional assessments at 6 and 12 months included remission (RI = 0 and prednisolone <= 7.5 mg), rate of infections and infusion reactions. Descriptive statistics and logistic regression were applied.
Results
We included 115 patients (74.8 % male, 86.1 % Caucasian) of whom 33 (28.7 %) had pancreato-hepato-biliary disease, 22 (19.1 %) retroperitoneal and aortic disease, 19 (16.5 %) head and neck-limited disease and 41 (35.7 %) Mikulicz’ and systemic disease. The primary outcome was met by 80 patients (69.9 %) with no significant difference across phenotypes. Remission rate at 6 months was lower in retroperitoneal and aortic disease (4.5 %) than in the other phenotypes (18.2-36.6 %, p = 0.025) while the head and neck-limited phenotype had higher flare rate at 12 months than the others (38.9 % vs. 4.8-25.0 %, p = 0.005). In multivariable models, higher baseline RI and lower serum IgG4 associated with the primary outcome (p < 0.05).
Conclusions
In this multi-center study, effectiveness of RTX did not differ across phenotypes. Our data do, however, indicate post-RTX differences in remission rates and flare risk across the phenotypes, with potential implications for surveillance and maintenance therapy.
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Sayadi, Ahmed; Sandling, Johanna K.; Eloranta, Maija Leena; Jönsen, Andreas; Gunnarsson, Iva & Rantapää-Dahlqvist, Solbritt
[Show all 45 contributors for this article]
(2025).
Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus.
Lupus Science and Medicine.
ISSN 2053-8790.
12(1).
doi:
10.1136/lupus-2024-001436.
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Background: SLE is a systemic autoimmune disease with a large number of common risk gene variants, but several rare gene variants can cause monogenic SLE. The relationship between common and rare variants in SLE is unclear. We therefore investigated the occurrence of rare deleterious variants in patients with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) and compared the frequency of these variants with their individual SLE polygenic risk score (PRS).
Materials and methods: Targeted sequencing of 1832 gene regions, including coding regions of 31 genes associated with monogenic SLE, was performed in 958 patients with SLE and 1026 healthy individuals. A total of 116 patients with SLE had disease onset before the age of 18 (cSLE). An SLE common variant PRS was created from 37 SLE genome-wide association study single nucleotide variants (SNVs).
Results: Rare coding deleterious SNVs (RD SNVs) were observed in 23 of the monogenic SLE-associated genes. Six per cent of patients with cSLE, compared with 3.2% of controls and 4.6% of patients with aSLE, carried rare deleterious alleles. In cSLE, RD SNVs were observed in the C1S, DDX58, IFIH1, IKZF1, RNASEH2A and C8A genes. A PRS analysis showed that patients with cSLE with any of these gene variants had a similar average PRS as control individuals.
Conclusion: RD SNVs were observed in a small proportion of cSLE and carriers of these RD SNVs had a PRS similar to healthy individuals, suggesting the importance of rare coding heterozygous variants in driving disease risk in a subset of children with SLE.
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Bjørkekjær, Hilde Jenssen; Bruni, Cosimo; Broch, Kaspar; Brunborg, Cathrine; Carreira, Patricia E & Airò, Paolo
[Show all 63 contributors for this article]
(2025).
A comparative analysis of risk stratification tools in SSc-associated pulmonary arterial hypertension: a EUSTAR analysis.
Rheumatology.
ISSN 1462-0324.
64(6),
p. 3643–3656.
doi:
10.1093/rheumatology/keaf053.
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Objectives
The 2022 European Society of Cardiology and European Respiratory Society (ESC/ERS) guidelines for pulmonary arterial hypertension (PAH) recommend risk stratification to optimize management. However, the performance of generic PAH risk stratification tools in patients with SSc-associated PAH remains unclear. Our objective was to identify the most accurate approach for risk stratification at SSc-PAH diagnosis.
Methods
In this multicentre, international cohort study from the European Scleroderma Trials and Research (EUSTAR) group database, we screened 11 risk stratification tools upon SSc-PAH diagnosis. We compared the performance of the three top-ranked tools to predict mortality with the ESC/ERS three-strata model, the currently recommended tool for baseline risk assessment. We also assessed the impact of incorporating SSc-specific characteristics into the tools. Kaplan–Meier analyses and Cox regression with area under the ROC curve (AUC) were conducted.
Results
The ESC/ERS three-strata model had a lower ability to predict mortality than the ESC/ERS four-strata model, ‘SPAHR updated’ and ‘REVEAL Lite 2’. The ESC/ERS four-strata model divided ‘intermediate-risk’ patients into two groups with significantly different long-term survival rates and is the easiest applicable tool. Incorporating SSc-specific characteristics did not significantly improve the predictive ability of any model, but a low diffusing capacity of the lung for carbon monoxide (DLCO) was an independent predictor of mortality.
Conclusion
Considering its ability to predict mortality, risk segregation capabilities and clinical applicability, this study provides a rationale for using the simplified ESC/ERS four-strata model at SSc-PAH diagnosis as an alternative to the comprehensive ESC/ERS three-strata model. We propose considering DLCO as an individual prognostic marker in SSc-PAH.
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Kilian, Karin; Brunborg, Cathrine; Holme, Sigrun Skaar; Garen, Torhild; Gunnarsson, Ragnar & Molberg, Øyvind
(2025).
Incidence and prevalence of ANCA-associated vasculitis in Oslo, Norway, applying different criteria-based case definitions: a population-based cohort study.
RMD Open.
11(3),
p. 005526–005526.
doi:
10.1136/rmdopen-2025-005526.
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Objective To provide complete data on the incidence and prevalence of antineutrophil cytoplasmic antibody-associated vasculitides (AAV) over the years 2000–2016 in the Oslo area, Norway, with 528 924 adults (aged 18+) in 2016. Methods From administrative databases, we identified all cases with International Classification of Disease, 10th Revision (ICD-10) codes indicative of necrotising small vessel vasculitis during 2000–2016 in the Oslo area. We manually chart reviewed every case identified through the ICD-10 search to confirm (or reject) a clinical AAV diagnosis. Cases with confirmed clinical AAV were classified by the European Medicine Agency (EMA) algorithm and the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR 2022) classification criteria. Results Among 469 cases with an ICD-10 code indicative of small vessel vasculitis, chart review confirmed AAV in 133 cases with 97 having new onset during the study. Of these 97 incident cases, 57 (60%) were classified as granulomatosis with polyangiitis (GPA), 29 (31%) as microscopic polyangiitis (MPA) and 9 (9%) as eosinophilic granulomatosis with polyangiitis (EGPA) per ACR/EULAR 2022 criteria, while 2 remained unclassified. There was an 11% discordance in AAV case classification between the 2022 criteria and the EMA algorithm. The mean annual incidence of AAV in adults was 12.2 per million (7.3 for GPA, 3.7 for MPA and 1.2 for EGPA). Across the study period, incidence rates increased numerically, and prevalence peaked at 143.7 AAV cases/million adults in 2016. Conclusion This population-based study adds new evidence that AAV increases in Europe and indicates that using the ACR/EULAR 2022 criteria shifts cases from GPA to MPA relative to the EMA algorithm, affecting epidemiology estimates.
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Haaversen, Anne Christine Bull; Brekke, Lene Kristin; Kermani, Tanaz A.; Molberg, Øyvind & Diamantopoulos, Andreas
(2025).
Ultrasonography Compared With Computed Tomography in Identifying Thoracic Aortic Aneurysms in Patients With Giant Cell Arteritis.
Arthritis care & research.
ISSN 2151-464X.
doi:
10.1002/acr.25657.
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Objective
The objectives of this study were to evaluate the correlation and agreement between ultrasonography and computed tomography (CT) in measuring ascending aorta diameter in patients with giant cell arteritis (GCA) and to investigate the development of new ascending aortic aneurysms in patients with newly diagnosed GCA.
Methods
To achieve the primary objective, we performed a cross-sectional study that included patients with GCA who were evaluated with both ultrasonography and CT of the ascending aorta within six months of each other. For the second objective, patients with baseline aortic imaging at GCA diagnosis were observed prospectively with new aortic imaging at the end of the follow-up. A cutoff of ≥40 mm defined an aneurysm in both the ascending and the descending aorta.
Results
The cross-sectional study included 140 patients with a total of 169 comparable CT and ultrasonography scans and a mean disease duration of 47.8 months (95% confidence interval [CI] 42.1–53.5). A strong positive correlation, as measured by Spearman's rho (r = 0.801, P < 0.001), and a strong agreement, as indicated by an intraclass correlation coefficient of 0.849 (P < 0.001), were found between ultrasonography and CT. In the prospective follow-up study, 40 patients were included. Seven (17.5%) patients developed aneurysms in the ascending aorta in a mean follow-up time of 54 months (95% CI 43.7–64.6); all of the patients experienced large vessel (LV) involvement (two patients with LV-GCA and five patients with mixed-GCA).
Conclusion
A strong correlation and agreement were observed between ultrasonography and CT measurements in assessing the diameter of the ascending aorta in patients with GCA. Ultrasonography may be a valuable tool for longitudinal monitoring and screening for aneurysm development. About 18% of patients developed aortic aneurysms over a mean follow-up of 4.5 years, underscoring the critical need for regular aortic screening in this population.
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Tengesdal, Stig; Molberg, Øyvind; Holme, Øyvind; Gran, Jan Tore & Myklebust, Geirmund
(2025).
Mortality in polymyalgia rheumatica: a 38-year prospective population-based cohort study from Southern Norway.
Arthritis Research & Therapy.
ISSN 1478-6354.
27,
p. 1–9.
doi:
10.1186/s13075-025-03613-9.
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Abstract Background Robust long-term mortality data on patients with polymyalgia rheumatica (PMR) are lacking. The aim of this study was to determine all-cause mortality in isolated PMR using a large, population-based, inception cohort followed prospectively over a 38-year period. Methods Between 1987 and 1997, 337 incident cases of PMR and biopsy-proven GCA were included in a prospective, population-based inception cohort in Aust-Agder County, Norway. Diagnosis was ascertained clinically by a rheumatologist, with PMR cases meeting Bird`s criteria. Patients were followed until death or end of study on December 31st, 2024. Each case was matched by gender, age at inclusion, and residency with 15 population comparators drawn from the population registry in Norway. We assessed mortality and survival by standard mortality ratios (SMR) and the Kaplan-Meier method. Results A total of 274 patients with isolated PMR (66.1% female, mean age at diagnosis 71.9 years) and 63 patients with GCA (76.2% female, mean age at diagnosis 71.6 years) were included. By the end of the study, 96.4% of all patients were deceased. Mean follow-up time for all patients was 13.7 years, with a maximum of 35.3 years. For cases with isolated PMR, the overall SMR was 0.97 (95% confidence interval [CI] 0.85, 1.09), for men 0.77 (95% CI 0.62, 0.95), and for women 1.11 (95% CI 0.95, 1.28). For GCA, the overall SMR was 1.10 (95% CI 0.85, 1.40), with no gender difference. Conclusions In this comprehensive long-term follow-up study with nearly complete data on mortality, isolated PMR was not associated with increased mortality, reinforcing the view that it does not confer a higher mortality risk.
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Moe, Sigrid Reppe; Haukeland, Hilde; Brunborg, Cathrine; Botea, Antonela; Damjanic, Nenad & Wivestad, Gro Årthun
[Show all 13 contributors for this article]
(2025).
Accrual of thromboembolic events and antiphospholipid syndrome in new-onset systemic lupus erythematosus: a population-based inception cohort study.
RMD Open.
11(3),
p. 005795–005795.
doi:
10.1136/rmdopen-2025-005795.
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Objective This population-based study aimed to determine timing and incidence of arterial and venous thromboembolic events (TE) and antiphospholipid syndrome (APS) relative to systemic lupus erythematosus (SLE) onset and assess relationships between TE, APS and anti-phospholipid antibodies (aPL) during follow-up. Methods We included all medical-record confirmed new-onset SLE patients in Southeast Norway (population 2.9 million) 2000–2017 who fulfilled the 2019 European Alliance of Rheumatology Associations/American College of Rheumatology classification criteria. APS was defined by the 2006 Sydney classification criteria, and aPL positivity was determined following international guidelines. Key outcomes were APS, TE and death. We estimated outcome-free survival using Kaplan-Meier methods. Results Among 700 new-onset SLE patients followed for a mean of 8 years (SD 5.0), 13% (89/700) experienced a new TE. TE incidence peaked at 59 per 100 person-years (95% CI 38 to 87) in the first year of SLE among aPL positive patients diagnosed with APS, falling to 12 (95% CI 6.2 to 21) in the subsequent 4 years. In patients without APS, corresponding TE incidences were 2.6 (95% CI 1.4 to 4.3) and 0.9 (95% CI 0.5 to 1.4), respectively. The lowest TE incidence was in aPL-negative patients aged <50 years, with 1-year TE-free survival of 0.99 (95% CI 0.97 to 1.0). Beyond the first year, TE-free survival rates did not differ between SLE patients positive and negative for aPL. Standardised mortality rate in patients with and without APS was 4.7 (95% CI 1.8 to 10.7 and 1.7 (95% CI 1.2 to 2.3). Conclusions This population-level study reveals high risk of TE, particularly for aPL positive patients around the time of SLE diagnosis. The elevated TE risk requires attention and early preventive strategies in newly diagnosed SLE.
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Bardan, Imane; Uhlig, Till; Sexton, Joseph; Kvien, Tore Kristian Aaserud; Bakland, Gunnstein & Pawel, Mielnik
[Show all 10 contributors for this article]
(2025).
Health-related Quality of Life in DMARD-treated adults with Juvenile Idiopathic Arthritis Compared to Rheumatoid Arthritis and the General Population.
Journal of Rheumatology.
ISSN 0315-162X.
p. 0384–0384.
doi:
10.3899/jrheum.2025-0384.
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Objective To explore health-related quality of life (HRQoL) measured by Short Form 36 (SF-36), SF-36 physical component score (PCS), SF-36 mental component score (MCS) and Short Form 6D (SF-6D) in adults with juvenile idiopathic arthritis (JIA) compared to rheumatoid arthritis (RA) and the general population. Methods We used six-month follow-up data from the Norwegian disease-modifying antirheumatic drug study (NOR-DMARD), including adult JIA and RA patients starting or switching disease-modifying anti-rheumatic drug (DMARD) treatment. Age- and gender adjusted regression analyses were used to compare outcomes between JIA, RA and the general Norwegian population. Results Register data was available for 232 JIA- and 2764 RA patients at six months follow-up. JIA patients had poorer physical, but similar mental health as RA (adjusted difference (95% CI): PCS -3.58 (-6.09 to -1.08); MCS 2.02 (-0.51 to 4.54)). Compared to the general population, PCS scores were lower in both JIA and RA (adjusted differences; JIA-general population: -15.70 (-18.21 to -13.19), RA-general population: -12.12 (-12.76 to -11.47), but MCS was similar across groups. Average SF-6D utility levels were comparable in JIA and RA, but lower than the general population. Similar proportions of JIA and RA experienced improvements exceeding minimal clinical important difference (MCID) in SF-36 scale scores, PCS, MCS and SF-6D after six months. Conclusion Compared to RA and the general population, JIA had lower physical HRQoL six months after DMARD initiation. Mental health composite scores were similar between JIA, RA and the general population. Both disease groups showed similar levels of improvement with treatment.
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Hoffmann-Vold, Anna-Maria; Kastrati, K.; Sprecher, M.; Langballe, Ellen Melbye; Diep, Phuong Phuong & Fretheim, Håvard Halland
[Show all 18 contributors for this article]
(2025).
ABS0838 IMPROVING EARLY ILD DETECTION IN SJÖGREN DISEASE: A RISK ESTIMATION TOOL FOR CLINICAL PRACTICE.
Annals of the Rheumatic Diseases.
ISSN 0003-4967.
84,
p. 2094–2095.
doi:
10.1016/j.ard.2025.06.1699.
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Interstitial lung disease (ILD) affects 10-15% of patients with Sjögren's disease (SjD), leading to increased morbidity and mortality. Early detection is crucial for optimizing disease management and improving patient outcomes. Current guidelines recommend screening SjD patients at-risk for ILD using high-resolution computed tomography (HRCT). To date, risk factor-based estimation tools for ILD in SjD patients are there are no criteria for referral to HRCT in clinical practice.
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Tschalèr, Lucas; Jordan, Suzana; Aaløkken, Trond Mogens; Becker, Mike; Brunborg, Cathrine & Bruni, Cosimo
[Show all 18 contributors for this article]
(2025).
Validation of a semi-quantitative method to assess interstitial lung disease severity and progression in systemic sclerosis by standard and low-dose HRCT scans.
RMD Open.
11(1).
doi:
10.1136/rmdopen-2024-004938.
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Background
While the presence of distinct imaging abnormalities by high-resolution CT (HRCT) defines interstitial lung disease (ILD), there is a relative lack of validated methods to quantify these abnormalities in clinical practice, limiting ILD severity and progression assessments. We aimed to validate a semi-quantitative method for lung fibrosis assessment in patients with systemic sclerosis associated ILD (SSc-ILD) by standard and low-dose HRCT, considering lung structure and function as integral components of ILD evaluation.
Methods
SSc patients from Oslo and Zurich with HRCT images, pulmonary function tests, including forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO) and the 6-minute walk test with oxygen (O2) desaturation were enrolled. We validated the semi-quantitative fibrosis extent method by HRCT using criteria for content and construct validity, discrimination, sensitivity to change and feasibility, as well as inter- and intra-rater variability.
Results
65 SSc patients from Zurich and 90 from Oslo were included. Significant correlations were observed between the extent of fibrosis on HRCT and FVC (r=−0.517, p<0.001), DLCO (r=−0.400, p<0.001) and O2 desaturation (r=−0.500, p<0.001), indicating content, construct and criterion validity. Discrimination and sensitivity to change assessments showed moderate correlation with DLCO (r=−0.377, p=0.003) but not with FVC or O2 desaturation. Inter- and intra-rater variability demonstrated excellent reliability (κ=0.891 and κ=0.996, respectively), with HRCT quantification averaging 9–15 min, indicating high feasibility.
Conclusion
This study confirms that semi-quantitative fibrosis assessment of HRCT for SSc-ILD meets most validation criteria, supporting its use in clinical practice and showing additive value of structural to functional ILD assessment.
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Fretheim, Håvard Halland; Barua, Imon Shoumitra; Bakland, Gunnstein; Dhainaut, Alvilde Sofie Strand; Halse, Anne Kristine Hjorteseth & Nordgård, Maylen Carstens
[Show all 21 contributors for this article]
(2025).
Faecal microbiota transplantation in patients with systemic sclerosis and lower gastrointestinal tract symptoms in Norway (ReSScue): a phase 2, randomised, double-blind, placebo-controlled trial.
The Lancet Rheumatology.
7(5),
p. e323–e332.
doi:
10.1016/S2665-9913(24)00334-5.
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Background: Gastrointestinal tract involvement is highly prevalent in systemic sclerosis, with few treatment options. We assessed the efficacy and safety of faecal microbiota transplantation using standardised anaerobic cultivated human intestinal microbiome (ACHIM) as a novel treatment option for patients with systemic sclerosis and symptomatic lower gastrointestinal tract involvement.
Methods: In this phase 2, randomised, double-blind, placebo-controlled trial done at four university hospitals in Norway, we enrolled adults aged 18-85 years with systemic sclerosis and moderate-to-severe lower gastrointestinal tract symptoms (bloating or diarrhoea). Participants were randomly assigned 1:1 to intestinal infusions of placebo or ACHIM at weeks 0 and 2, stratified by worst symptom (bloating or diarrhoea). The primary endpoint was change in worst lower gastrointestinal tract symptom (bloating or diarrhoea) from week 0 to week 12, measured using the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 scoring system in the intention-to-treat population. Safety was assessed at weeks 0, 2, 4, 6, and 12 in all participants who received at least one infusion. A person with lived experience of systemic sclerosis was involved in the study planning and conduct. This trial was registered at ClinicalTrials.gov, NCT04300426.
Findings: Between Sept 24, 2020, and Jan 14, 2022, 67 participants were enrolled and randomly allocated to placebo (n=34) or ACHIM (n=33). Mean age was 58·91 years (SD 11·59). 62 (93%) of 67 participants were women, five (7%) were men, and 50 (75%) were anti-centromere antibody positive. Change in worst lower gastrointestinal tract symptom from week 0 to week 12 did not differ between participants who received ACHIM (-0·13, 95% CI -0·37 to 0·11) and participants who received placebo (-0·33, -0·57 to -0·09; average marginal effect 0·20, 95% CI -0·12 to 0·52; p=0·22). Adverse events, mostly mild and short-lived gastrointestinal tract symptoms, were reported by 16 (48%) of 33 participants in the ACHIM group and 19 (56%) of 34 in the placebo group. During gastroscopy, one participant had a duodenal perforation.
Interpretation: Faecal microbiota transplantation with ACHIM was well tolerated in participants with systemic sclerosis but did not result in an improvement in lower gastrointestinal tract symptoms.
Funding: KLINBEFORSK.
Translation: For the Norwegian translation of the abstract see Supplementary Materials section.
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Haukeland, Hilde; Moe, Sigrid Reppe; Brunborg, Cathrine; Botea, Antonela; Damjanic, Nenad & Wivestad, Gro Årthun
[Show all 13 contributors for this article]
(2024).
Sensitivity of classification criteria from time of diagnosis in an incident systemic lupus erythematosus cohort: a population-based study from Norway.
RMD Open.
10(3).
doi:
10.1136/rmdopen-2024-004395.
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Objectives To compare the sensitivity of 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria against 1997 ACR criteria for systemic lupus erythematosus (SLE), for incident SLE cases in the presumably complete population-based Nor-SLE cohort from Southeast Norway (2.9 million inhabitants). Methods All cases International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coded as SLE during 2000–2017 were individually reviewed. Those with a confirmed SLE diagnosis by expert clinical assessment were included in the Nor-SLE cohort. Core clinical data were recorded, and the cases were classified according to 2019 EULAR/ACR and 1997 ACR criteria. Juvenile SLE was defined as <16 years at diagnosis and adult SLE was defined as ≥16 years at diagnosis. Results We included 737 incident SLE cases (701 adults, 36 juveniles). At diagnosis, 2019 EULAR/ACR criteria were more sensitive than 1997 ACR criteria for adults (91.6% vs 77.3%; p<0.001), but not for juveniles (97.2% vs 88.9%). The 2019 EULAR/ACR counts at diagnosis differed by age group and ethnicity, being higher in young cases and those originating from Asia. From time of diagnosis to study end the fulfilment rate of 2019 EULAR/ACR criteria for the adult cohort increased from 92.5% and 86.5% to 94.6% and 91.0%, respectively, for females and males (mean disease duration of 7.5 years). Conclusion Showing 92% criteria fulfilment already at time of SLE diagnosis by 2019 EULAR/ACR criteria versus 77% by 1997 ACR criteria, the results from this population-based study suggest that the 2019 EULAR/ACR criteria will achieve its goal of capturing more early-SLE cases for clinical trials.
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Bianchi, Matteo; Kozyrev, Sergey V.; Notarnicola, Antonella; Sandling, Johanna K.; Pettersson, Mats & Leonard, Dag
[Show all 33 contributors for this article]
(2024).
Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases.
Arthritis & Rheumatology.
ISSN 2326-5191.
77(2).
doi:
10.1002/art.42988.
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Objective Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features. Methods We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments. Results Case–control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case–case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti–double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders. Conclusion Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.
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Haaversen, Anne Christine Bull; Brekke, Lene Kristin; Kermani, Tanaz A.; Molberg, Øyvind & Diamantopoulos, Andreas P
(2024).
Vascular ultrasound as a follow-up tool in patients with giant cell arteritis: a prospective observational cohort study.
Frontiers in Medicine.
11.
doi:
10.3389/fmed.2024.1436707.
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Objectives: To evaluate relapses in giant cell arteritis (GCA), investigate the utility of vascular ultrasound to detect relapses, and develop and assess a composite score for GCA disease activity (GCAS) based on clinical symptoms, ultrasound imaging activity, and C-reactive protein (CRP). Methods: Patients with GCA were prospectively followed with scheduled visits, including assessment for clinical relapse, protocol ultrasound examination, and CRP. At each visit, patients were defined as having ultrasound remission or relapse. GCAS was calculated at every visit. Results: The study included 132 patients, with a median follow-up time of 25 months [interquartile range (IR) 21]. The clinical relapse rate was 60.6%. There were no differences in relapse rates between GCA subtypes (cranial-GCA, large vessel (LV)-GCA, and mixed-GCA) (p = 0.83). Ultrasound yielded a sensitivity of 61.2% and a specificity of 72.3% for diagnosing GCA- relapse in our cohort. In 7.7% of follow-up visits with clinical relapses, neither high CRP nor findings of ultrasound relapse were registered. In comparison, in 10.3% of follow-up visits without symptoms of clinical relapse, there were both a high CRP and findings of ultrasound relapse. Conclusion: We found moderate sensitivity and specificity for ultrasound as a monitoring tool for relapse in this prospective cohort of GCA patients. The extent or subtype of vasculitis at the diagnosis did not influence the number of relapses. Based on a combination of clinical symptoms, elevated CRP, and ultrasound findings, a composite score for GCA activity is proposed.
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Marstein, Henriette; NOMELAND, BIRGIT; Godang, Kristin; Olarescu, Nicoleta Cristina; Schwartz, Thomas & Flatø, Berit
[Show all 10 contributors for this article]
(2023).
Adipokine profile in long-term juvenile dermatomyositis, and associations with adipose tissue distribution and cardiac function: a cross-sectional study.
RMD Open.
9:e002815(1),
p. 1–9.
doi:
10.1136/rmdopen-2022-002815.
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Objectives In long-term juvenile dermatomyositis (JDM), altered adipose tissue distribution and subclinical cardiac dysfunction have been described. Our aims were to compare adipokine levels in patients with JDM after long-term disease with controls, and explore associations between adipokines and (1) adipose tissue distribution and (2) cardiac function. Methods The study cohort included 59 patients with JDM (60% female, mean age 25.2 years, mean disease duration 16.9 years), and 59 age/sex-matched controls. Updated Pediatric Rheumatology International Trials Organization criteria for clinically inactive JDM were used to stratify patients into active (JDM-active) or inactive (JDM-inactive) disease groups. Lipodystrophy was clinically assessed in all patients. In all study participants, we measured adipose tissue distribution by dual-energy X-ray absorptiometry and cardiac function by echocardiography. Serum adipokines (adiponectin, apelin-12, lipocalin-2, leptin, visfatin and resistin) were analysed using ELISA. Results Patients with JDM had higher leptin levels compared with controls (p≤0.01). In JDM-active, apelin-12 and visfatin were higher compared with JDM-inactive (p≤0.05). In JDM-total and JDM-active, lower adiponectin correlated with lipodystrophy and total fat mass. Also, systolic dysfunction correlated with: lower adiponectin in JDM-total, JDM-inactive and JDM-active, and with lower apelin-12 in JDM-total and JDM-active and resistin in JDM-active (all p≤0.05). Lower adiponectin correlated with diastolic dysfunction in JDM-total and JDM-active. Conclusion After long-term disease, leptin levels were unfavourably regulated in patients with JDM compared with controls, and apelin-12 and visfatin in JDM-active versus JDM-inactive. We found associations between adipokines and both adipose tissue distribution and cardiac systolic function in all patients with JDM, which was most prominent in patients with active disease.
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Haukeland, Hilde; Moe, Sigrid Reppe; Brunborg, Cathrine; Botea, Antonela; Damjanic, Nenad & Wivestad, Gro Årthun
[Show all 12 contributors for this article]
(2023).
Declining Incidence of Systemic Lupus Erythematosus in Norway 1999–2017: Data From a Population Cohort Identified by International Classification of Diseases, 10th Revision Code and Verified by Classification.
Arthritis & Rheumatology.
ISSN 2326-5191.
doi:
10.1002/art.42775.
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Objective: To provide complete, robust data on annual SLE incidence rates over nearly two decades from the Southeast Norway area (2.9 million inhabitants) and assess accuracy of SLE-specific ICD codes for SLE diagnosis.
Methods: From administrative databases, we identified all cases ICD-10 coded as SLE during 1999-2017 in Southeast Norway. We manually reviewed the chart of every case ICD-10 coded as SLE to either confirm or reject SLE diagnosis. Using SLE classification criteria, we classified all cases with confirmed SLE. We estimated annual incidence rates of classified SLE, and subsets, defined by age at diagnosis, sex, and parental country of birth. Chi-square test was applied for linear time-trend analyses of incidence.
Results: Among the 3488 cases ICD-10 coded as SLE, chart-reviews confirmed SLE diagnosis in 1558 (45%), of which 797 had new-onset disease during 1999-2017. Annual SLE incidence-rates fell during 1999-2017. The fall was most pronounced in female subjects aged 50-59 years at diagnosis where incidence fell from 3.4 to 1.1 per 100 000 (p-trend <0.001). Concurrent ecological data from the study area showed a 74% reduction in prescriptions of menopausal hormone treatment. Accuracy of ICD-10 codes for incident SLE diagnosis was acceptable in juveniles and young adults (up to 20 years) but otherwise low.
Conclusion: In a presumably complete population-based cohort, we identified decreasing incidence of SLE, especially among female subjects aged 50-59 years. While reasons for declining incidence are not clear, ecological data indicate a possible role of environmental factors, for example menopausal hormone treatments.
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Berger, Simon Girmai; NOMELAND, BIRGIT; Reiseter, Silje; Schwartz, Thomas; Andersson, Anna Helena & Hetlevik, Siri Opsahl
[Show all 13 contributors for this article]
(2023).
Cardiac dysfunction in mixed connective tissue disease: a nationwide observational study.
Rheumatology International.
ISSN 0172-8172.
p. 1055–1065.
doi:
10.1007/s00296-023-05308-3.
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Abstract We aimed to identify cardiac function in patients with established mixed connective tissue disease (MCTD). This was a cross-sectional case–control study of well-characterised MCTD patients who had previously been included in a nationwide cohort. Assessments comprised protocol transthoracic echocardiography, electrocardiogram and blood samples. In patients only, we evaluated the findings of high-resolution pulmonary computed tomography and disease activity. We assessed 77 MCTD patients (mean age 50.5 ± 12.3 years) with a mean disease duration of 16.4 years, and 59 age- and sex-matched healthy controls (49.9 ± 11.7 years). By echocardiography, measures of left ventricular function, i.e. fractional shortening (38.1 ± 6.4% vs. 42.3 ± 6.6%, p < 0.001), mitral annulus plane systolic excursion (MAPSE) (13.7 ± 2.1 mm vs. 15.3 ± 2.3 mm, p < 0.001) and early diastolic velocity of the mitral annulus (e’) (0.09 ± 0.02 m/s vs. 0.11 ± 0.03 m/s, p = 0.002) were subclinical and lower in patients than controls. Right ventricular dysfunction was found in patients assessed by tricuspid annular plane systolic excursion (TAPSE) (22.7 ± 4.0 mm vs. 25.5 ± 4.0 mm, p < 0.001). While cardiac dysfunction was not associated with pulmonary disease, e’ and TAPSE were found to correlate with disease activity at baseline. In this cohort of MCTD patients, echocardiographic examinations demonstrated a higher frequency of cardiac dysfunction than in matched controls. Cardiac dysfunction was associated with disease activity at baseline, but was independent of cardiovascular risk factors and pulmonary disease. Our study indicates that cardiac dysfunction is part of the multi-organ affliction seen in MCTD.
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Strahm, Noemi; Didriksen, Henriette; Fretheim, Håvard Halland; Molberg, Øyvind; Midtvedt, Øyvind & Farstad, Inger Nina
[Show all 13 contributors for this article]
(2023).
Effects of faecal microbiota transplantation on the small intestinal mucosa in systemic sclerosis.
Rheumatology.
ISSN 1462-0324.
62(8),
p. 2918–2929.
doi:
10.1093/rheumatology/kead014.
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Abstract Objectives In SSc, gastrointestinal tract (GIT) involvement is a major concern, with no disease-modifying and limited symptomatic therapies available. Faecal microbiota transplantation (FMT) represents a new therapeutic option for GIT-affliction in SSc, showing clinical promise in a recent controlled pilot trial. Here, we aim to investigate effects of FMT on duodenal biopsies collected from SSc patients by immunohistochemistry and transcriptome profiling. Methods We analysed duodenal biopsies obtained pre-intervention (week 0) and post-intervention (weeks 2 and 16) from nine SSc patients receiving an intestinal infusion of FMT (n = 5) or placebo (n = 4). The analysis included immunohistochemistry (IHC) with a selected immune function and fibrosis markers, and whole biopsy transcriptome profiling. Results In patients receiving FMT, the number of podoplanin- and CD64-expressing cells in the mucosa were lower at week 2 compared with baseline. This decline in podoplanin- (r = 0.94) and CD64-positive (r = 0.89) cells correlated with improved patient-reported lower GIT symptoms. Whole biopsy transcriptome profiling from week 2 showed significant enrichment of pathways critical for cellular and endoplasmic reticulum stress responses, microvillus and secretory vesicles, vascular and sodium-dependent transport, and circadian rhythm. At week 16, we found enrichment of pathways mandatory for binding activity of immunoglobulin receptors, T cell receptor complexes, and chemokine receptors, as well as response to zinc-ions. We found that 25 genes, including Matrix metalloproteinase-1 were upregulated at both week 2 and week 16. Conclusion Combining selective IHC and unbiased gene expression analyses, this exploratory study highlights the potential for disease-relevant organ effects of FMT in SSc patients with GIT involvement. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03444220.
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Vikse, Jens; Midtvedt, Øyvind; Fevang, Bjørg Tilde Svanes; Garen, Torhild Oddveig; Palm, Øyvind & Wallenius, Marianne
[Show all 10 contributors for this article]
(2023).
Differential sensitivity of the 2020 revised comprehensive diagnostic criteria and the 2019 ACR/EULAR classification criteria across IgG4-related disease phenotypes: results from a Norwegian cohort.
Arthritis Research & Therapy.
ISSN 1478-6354.
25(1).
doi:
10.1186/s13075-023-03155-y.
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Background We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: “Pancreato-Hepato-Biliary”, “Retroperitoneum and Aorta”, “Head and Neck-limited” and “Mikulicz’ and Systemic” in a well-characterized patient cohort. Methods We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. Results The study cohort included 79 IgG4-RD patients assigned to the “Pancreato-Hepato-Biliary” (22.8%), Retroperitoneum and Aorta” (22.8%) “Head and Neck-limited” (29.1%), and “Mikulicz’ and Systemic” (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the “Retroperitoneum and Aorta” group (66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the “Retroperitoneum and Aorta” group (27.8%, p < 0.001). Conclusion The results from this study indicate that IgG4-RD patients having the “Retroperitoneum and Aorta” phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.
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Leclair, Valérie; Galindo-Feria, Angeles S.; Rothwell, Simon; Kryštůfková, Olga; Zargar, Sepehr Sarrafzadeh & Mann, Herman
[Show all 23 contributors for this article]
(2023).
Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies.
EBioMedicine.
96.
doi:
10.1016/j.ebiom.2023.104804.
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Background In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. Methods We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or –associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. Findings We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1 or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1 subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1 and the negative subgroup. Interpretation Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features.
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Moe, Sigrid Reppe; Haukeland, Hilde; Brunborg, Cathrine; Botea, Antonela; Damjanic, Nenad & Wivestad, Gro Årthun
[Show all 14 contributors for this article]
(2023).
Persisting mortality gap in systemic lupus erythematosus; a population-based study on juvenile- and adult-onset SLE in Norway 1999–2022.
Rheumatology.
ISSN 1462-0324.
63(8),
p. 2109–2117.
doi:
10.1093/rheumatology/kead519.
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Objective: To estimate mortality and survival rates of systemic lupus erythematosus (SLE) in a contemporary, population-based setting and assess potential influences by time, sex, ethnicity, classification criteria and age at diagnosis.
Methods: We assessed mortality and survival in the Nor-SLE cohort, which includes all chart-review confirmed SLE cases resident in Southeast Norway (population 2.9 million) 1999-2017. Study end was at death, emigration, or 1 October 2022. We defined juvenile SLE by age <16 years at diagnosis. For standardized mortality rate (SMR) estimates, we applied 15 population controls per case, all matched for age, sex, residency, and ethnicity. We analyzed survival by Kaplan-Meier and risk factors by cox regression.
Results: The Nor-SLE cohort included 1558 SLE cases, of whom 749 were incident and met the 2019 European Alliance of Associations for Rheumatology and American College of Rheumatology (2019-EA) classification criteria. SMR was increased to 1.8 (95% CI 1.6-2.2) in incident adult-onset SLE but did not differ between females and males. Survival rates at 5-, 10-, 15 and 20-years were lower in incident adult-onset SLE than in matched controls. In multivariable analysis, lupus nephritis associated with decreased survival, while sex did not. Separate, long-term mortality analyses in the total Nor-SLE cohort showed that SMR peaked at 7.2 (95% CI 3.3-14) in juvenile-onset SLE (n = 93) and fell gradually by increasing age at SLE diagnosis.
Conclusion: This study shows persistence of a mortality gap between adult-onset SLE and controls at population level and provides indications of worryingly high mortality in juvenile-onset SLE.
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Lundtoft, Christian; Pucholt, Pascal; Martin, Myriam; Bianchi, Matteo; Lundström, Emeli & Eloranta, Maija-Leena
[Show all 49 contributors for this article]
(2022).
Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases.
Arthritis & Rheumatology.
ISSN 2326-5191.
74(8),
p. 1440–1450.
doi:
10.1002/art.42122.
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Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2–33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7–5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals’ capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
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Haaversen, Anne Christine Bull; Brekke, Lene Kristin; Kermani, Tanaz A.; Molberg, Øyvind & Diamantopoulos, Andreas P
(2022).
Extended ultrasound examination identifies more large vessel involvement in patients with giant cell arteritis.
Rheumatology.
ISSN 1462-0324.
62(5),
p. 1887–1894.
doi:
10.1093/rheumatology/keac478.
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Didriksen, Henriette; Molberg, Øyvind; Mehta, Adi; Jordan, Suzana; Palchevskiy, Vyacheslav & Fretheim, Håvard Halland
[Show all 16 contributors for this article]
(2022).
Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension.
Frontiers in Immunology.
13.
doi:
10.3389/fimmu.2022.991743.
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Introduction Systemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21. Materials and methods To investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS). Results By IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p&lt;0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p&lt;0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail. Conclusion This study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.
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Leeuwen, Nina M. van; Boonstra, Maaike; Fretheim, Håvard Halland; Brunborg, Cathrine; Midtvedt, Øyvind & Garen, Torhild Oddveig
[Show all 10 contributors for this article]
(2022).
Gastrointestinal symptom severity and progression in systemic sclerosis.
Rheumatology.
ISSN 1462-0324.
61(10),
p. 4024–4034.
doi:
10.1093/rheumatology/keac118.
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Abstract Objectives To evaluate the severity and evolution of patient-reported gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc) patients, assess predictive factors for progression and determine the impact of standard of care treatment. Methods SSc patients from the Leiden and Oslo cohorts were included. We assessed clinical data and patient-reported GIT symptoms measured by the validated University of California, Los-Angeles Gastrointestinal-tract (UCLA-GIT) score at baseline and annually. GIT severity and progression was determined. Logistic regression was applied to identify risk factors associated with baseline GIT symptom severity. Linear mixed-effect models were applied to assess progression in GIT symptom burden and to identify predictive factors. We repeated all analysis in patients with early disease (inception cohort) to exclude the effect of longstanding disease and increase insights in development of GIT symptom burden early in the disease course. Results We included 834 SSc patients with baseline UCLA GIT scores, 454 from Leiden and 380 from Oslo. In the total cohort, 28% reported moderate-severe GIT symptoms at baseline, with increased risk for severity conferred by ACA, smoking and corticosteroid use, while use of calcium channel blockers appeared protective. In the inception cohort, 23% reported moderate-severe GIT symptoms at baseline, with increased risk for females and with smoking. Over time, symptom burden increased mainly for reflux/bloating. Female sex and ACA predicted GIT symptom progression. Conclusion High GIT symptom burden is present early in SSc disease course. Both for prevalence and for progression of GIT symptom burden, female sex and smoking were identified as risk factors.
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Tennøe, Anders; Murbræch, Klaus; Didriksen, Henriette; Ueland, Thor; Palchevskiy, Vyacheslav & Weigt, Stephen S.
[Show all 14 contributors for this article]
(2022).
Serum markers of cardiac complications in a systemic sclerosis cohort.
Scientific Reports.
12(4661 ).
doi:
10.1038/s41598-022-08815-8.
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Abstract Primary cardiac involvement is one of the leading causes of mortality in systemic sclerosis (SSc), but little is known regarding circulating biomarkers for cardiac SSc. Here, we aimed to investigate potential associations between cardiac SSc and candidate serum markers. Serum samples from patients of the Oslo University SSc cohort and 100 healthy controls were screened against two custom-made candidate marker panels containing molecules deemed relevant for cardiopulmonary and/or fibrotic diseases. Left (LV) and right ventricular (RV) dysfunction was assessed by protocol echocardiography, performed within three years from serum sampling. Patients suspected of pulmonary hypertension underwent right heart catheterization. Vital status at study end was available for all patients. Descriptive analyses, logistic and Cox regressions were conducted to assess associations between cardiac SSc and candidate serum markers. The 371 patients presented an average age of 57.2 (± 13.9) years. Female sex (84%) and limited cutaneous SSc (73%) were predominant. Association between LV diastolic dysfunction and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR 0.41, 95% CI 0.21–0.78, p = 0.007) was identified. LV systolic dysfunction defined by global longitudinal strain was associated with angiopoietin 2 (ANGPT2) (OR 3.42, 95% CI 1.52–7.71, p = 0.003) and osteopontin (OPN) (OR 1.95, 95% CI 1.08–3.52, p = 0.026). RV systolic dysfunction, measured by tricuspid annular plane systolic excursion, was associated to markers of LV dysfunction (ANGPT2, OPN, and TRAIL) (OR 1.67, 95% CI 1.11–2.50, p = 0.014, OR 1.86, 95% CI 1.25–2.77, p = 0.002, OR 0.32, 95% CI 0.15–0.66, p = 0.002, respectively) and endostatin (OR 1.86, 95% CI 1.22–2.84, p = 0.004). In conclusion, ANGPT2, OPN and TRAIL seem to be circulating biomarkers associated with both LV and RV dysfunction in SSc.
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Bardan, Imane; Fagerli, Karen Minde; Sexton, Joseph; Kvien, Tore Kristian Aaserud; Bakland, Gunnstein & Pawel, Mielnik
[Show all 12 contributors for this article]
(2022).
Treatment Response to Tumor Necrosis Factor Inhibitors and Methotrexate Monotherapy in Adults With Juvenile Idiopathic Arthritis: Data From NOR-DMARD.
Journal of Rheumatology.
ISSN 0315-162X.
50(4),
p. 538–547.
doi:
10.3899/JRHEUM.220645.
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Objective To compare the effectiveness of tumor necrosis factor inhibitors (TNFi) ± comedication and methotrexate (MTX) monotherapy between patients with adult juvenile idiopathic arthritis (JIA) and patients with rheumatoid arthritis (RA). Methods Adult patients with JIA and RA were identified from the Norwegian Antirheumatic Drug Register (NOR-DMARD) register. Disease activity measurements at baseline, 3, 6, and 12 months were compared between patients with JIA and RA starting (1) TNFi and (2) MTX monotherapy, using age- and gender-weighted analyses. We calculated differences between JIA and RA in mean changes in Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI), among other disease activity measures. DAS28, CDAI, SDAI, and American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) remission rates at 3, 6, and 12 months, as well as 6- and 12-month Lund Efficacy Index (LUNDEX)-corrected rates, were calculated. Results We identified 478 patients with JIA (TNFi/MTX monotherapy, n = 358/120) and 4637 patients with RA (TNFi/MTX monotherapy, n = 2292/2345). Patients with JIA had lower baseline disease activity compared to patients with RA across treatment groups. After baseline disease activity adjustment, there were no significant differences in disease activity change from baseline to 3, 6, and 12-months of follow-up between patients with JIA and RA for either treatment group. Twelve-month remission rates were similar between groups based on DAS28 (TNFi: JIA 55.2%, RA 49.5%; MTX monotherapy: JIA 45.3%, RA 41.2%) and ACR/EULAR remission criteria (TNFi: JIA 20.4%, RA 20%; MTX monotherapy: JIA 17%, RA 12.7%). Median drug survival (yrs) was similar for JIA and RA in both treatment groups (TNFi: JIA 1.2, RA 1.4; MTX monotherapy: JIA 1.3, RA 1.6). Conclusion TNFi and MTX monotherapy are effective in adult JIA, with similar effectiveness to that shown in RA.
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Matteo, Bianchi; Kozyrev, Sergey V.; Notarnicola, Antonella; Rosenberg, Lina Hultin; Karlsson, Åsa & Pucholt, Pascal
[Show all 22 contributors for this article]
(2021).
Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort.
Arthritis & Rheumatology.
ISSN 2326-5191.
74(2),
p. 342–352.
doi:
10.1002/art.41929.
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Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations. Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
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NOMELAND, BIRGIT; Bollerslev, Jens; Godang, Kristin; Schwartz, Thomas; Flatø, Berit & Molberg, Øyvind
[Show all 8 contributors for this article]
(2021).
Body composition in long-standing juvenile dermatomyositis: associations with disease activity, muscle strength and cardiometabolic measures.
Rheumatology.
ISSN 1462-0324.
61(7),
p. 2959–2968.
doi:
10.1093/rheumatology/keab805.
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Abstract Objective To (i) compare body composition parameters in patients with longstanding juvenile dermatomyositis (JDM) and controls and (ii) explore associations between body composition and disease activity/inflammation, muscle strength, health-related quality of life (HRQL) and cardiometabolic measures. Methods In a cross-sectional study, we included 59 patients (median disease duration 16.7 y; median age 21.5 y) and 59 age- and sex-matched controls. Active/inactive disease were defined by the PRINTO criteria. Body composition was assessed by total body dual-energy absorptiometry (DXA), inflammation by hs-CRP and cytokines, muscle strength by manual muscle test (MMT-8), HRQL by 36-item short form survey physical component score (SF-36 PCS) and cardiometabolic function by echocardiography (systolic and diastolic function) and serum-lipids. Results DXA analyses revealed lower appendicular lean mass index (ALMI) (reflecting limb skeletal muscle mass), higher body fat percentage (BF%) and higher android: gynoid fat ratio (A: G ratio) (reflecting central fat distribution) in patients than controls, despite similar BMI. Patients with active disease had lower ALMI and higher BF% than those with inactive disease; lower ALMI and higher BF% were associated with inflammation (elevated monocyte attractant protein-1 (MCP-1) and hs-CRP). Lower ALMI was associated with reduced muscle strength; higher BF% was associated with impaired HRQL. Central fat distribution (higher A: G ratio) was associated with impaired cardiac function and unfavorable serum-lipids. Conclusion : Despite normal BMI, patients with JDM, especially those with active disease, had unfavorable body composition, which was associated with impaired HRQL/muscle strength and cardiometabolic function. The association between central fat distribution and cardiometabolic alterations is a novel finding in JDM.
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Hoffmann-Vold, Anna-Maria; Fretheim, Håvard Halland; Sarna, Vikas Kumar; Barua, Imon Shoumitra; Nordgård, Maylen Carstens & Distler, Oliver
[Show all 16 contributors for this article]
(2021).
Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: Study protocol for the randomised controlled phase II ReSScue trial.
BMJ Open.
11(6).
doi:
10.1136/bmjopen-2020-048541.
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Introduction In the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture ‘Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)’. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc. Methods and analyses We aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating).
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Moe, Sigrid E Reppe; Haukeland, Hilde; Molberg, Øyvind & Lerang, Karoline
(2021).
Long-term outcome in systemic lupus erythematosus; knowledge from population-based cohorts.
Journal of Clinical Medicine.
10(19).
doi:
10.3390/jcm10194306.
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Background: Accurate knowledge of outcomes in Systemic Lupus Erythematosus (SLE) is crucial to understanding the true burden of the disease. The main objective of this systematic review was to gather all population-based studies on mortality, end-stage renal disease (ESRD) and cancer in SLE. Method: We performed a systematic literature search in two electronic databases (MEDLINE and Embase) to identify all population-based articles on SLE and survival, mortality, ESRD and cancer. The SLE diagnosis had to be verified. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). Results: We included 40/1041 articles on mortality (27), ESRD (11) and cancer (3), of which six were defined as inception studies. In the total SLE cohort, the standardized mortality ratio ranged from 1.9 to 4.6. Cardiovascular disease was the most frequent cause of death in studies with follow-up times over 15 years. SLE progressed to ESRD in 5–11% of all SLE patients. There are no data supporting increased cancer incidence from population-based inception cohorts. Conclusion: There is a need for more population-based studies on outcomes of SLE, especially inception studies, with the use of control groups and follow-up times over 15 years.
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Nyborg, Gunhild Alvik & Molberg, Øyvind
(2021).
Small intestinal biopsy findings consistent with celiac disease in patients with idiopathic inflammatory myopathy: Review of existing literature.
Seminars in Arthritis & Rheumatism.
ISSN 0049-0172.
51(5),
p. 1033–1044.
doi:
10.1016/j.semarthrit.2021.07.012.
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Background: Case reports have described patients with idiopathic inflammatory myopathies (IIM) and a concurrent diagnosis of celiac disease (CeD) for whom the muscle inflammation (myositis) component of IIM improves after the patients start standard treatment with gluten-free diet (GFD). A connection between IIM and CeD is not commonly recognized. Aim: In this first systematic review of the topic, we aimed to explore all peer-reviewed publications of IIM cases and concomitant small intestinal biopsy findings consistent with CeD, published after 1975. Methods: Systematic literature searches were performed in MEDLINE, PubMed, and EMBASE, supplemented by screening of references and non-systematic searches via Google and Google Scholar. Results: Altogether 30 cases published between 1976 and 2017 were uncovered. Information about gastrointestinal symptoms prior to CeD diagnosis was available for 19 patients, with 6/19 (32%) reporting no GI symptoms. CeD-related serological data were available in 23/30 patients. Endomysial antibodies were present in 10/18 (56%), while only 2/9 (22%) had antibodies against tissue transglutaminase. Serum antibodies to native gliadin were present in 16/18 (89%). Clinical effects of a GFD on the IIM were reported for 24 patients, with signs of improvement in 14/24 (58%), including three patients with otherwise therapy-resistant inclusion body myositis. Longitudinal follow-up data available from the published studies indicated that 7/24 (29%) remained in clinical IIM remission with GFD as the sole therapeutic intervention. Conclusion: In the IIM cases presented here, duodenal biopsy findings consistent with celiac disease was sometimes present without classical CeD symptoms or positive traditional CeD serology, and in the majority of cases, the IIM improved after introduction of a gluten-free diet. While extra vigilance towards CeD in IIM patients seems warranted, there is need for more research to clarify if GFD has effects on organ systems other than the small intestine in patients with IIM and small intestinal biopsy findings consistent with CeD.
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Holme, Sigrun Skaar; Kilian, Karin; Eggesbø, Heidi Beate; Moen, Jon Magnus & Molberg, Øyvind
(2021).
Impact of baseline clinical and radiological features on outcome of chronic rhinosinusitis in granulomatosis with polyangiitis.
Arthritis Research & Therapy.
ISSN 1478-6354.
23(18),
p. 1–11.
doi:
10.1186/s13075-020-02401-x.
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Background Granulomatosis with polyangiitis (GPA) causes a recurring inflammation in nose and paranasal sinuses that clinically resembles chronic rhinosinusitis (CRS) of other aetiologies. While sinonasal inflammation is not among the life-threatening features of GPA, patients report it to have major negative impact on quality of life. A relatively large proportion of GPA patients have severe CRS with extensive damage to nose and sinus structures evident by CT, but risk factors for severe CRS development remain largely unknown. In this study, we aimed to identify clinical and radiological predictors of CRS-related damage in GPA. Methods We included GPA patients who had clinical data sets from time of diagnosis, and two or more paranasal sinus CT scans obtained ≥12 months apart available for analysis. We defined time from first to last CT as the study observation period, and evaluated CRS development across this period using CT scores for inflammatory sinus bone thickening (osteitis), bone destructions, and sinus opacifications (here defined as mucosal disease). In logistic regression, we applied osteitis as main outcome measure for CRS-related damage. Results We evaluated 697 CT scans obtained over median 5 years observation from 116 GPA patients. We found that 39% (45/116) of the GPA patients remained free from CRS damage across the study observation period, while 33% (38/116) had progressive damage. By end of observation, 32% (37/116) of the GPA patients had developed severe osteitis. We identified mucosal disease at baseline as a predictor for osteitis (odds ratio 1.33), and we found that renal involvement at baseline was less common in patients with severe osteitis at last CT (41%, 15/37) than in patients with no osteitis (60%, 27/45). Conclusions In this largely unselected GPA patient cohort, baseline sinus mucosal disease associated with CRS-related damage, as measured by osteitis at the end of follow-up. We found no significant association with clinical factors, but the data set indicated an inverse relationship between renal involvement and severe sinonasal affliction.
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Sandling, Johanna K.; Pucholt, Pascal; Rosenberg, Lina Hultin; Farias, Fabiana H.G.; Kozyrev, Sergey V. & Eloranta, Maija-Leena
[Show all 32 contributors for this article]
(2021).
Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing.
Annals of the Rheumatic Diseases.
ISSN 0003-4967.
80,
p. 109–117.
doi:
10.1136/annrheumdis-2020-218636.
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Objectives Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
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Sikkeland, Liv Ingunn Bjoner; Qiao, Shuo Wang; Ueland, Thor; Myrdal, Ole Henrik; Wyrozemski, Lukasz Adam & Aukrust, Pål
[Show all 12 contributors for this article]
(2020).
Lung CD4+ T cells in patients with lung fibrosis produce pro-fibrotic IL-13 together with IFNγ.
European Respiratory Journal.
ISSN 0903-1936.
57:2000983(3),
p. 1–4.
doi:
10.1183/13993003.00983-2020.
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Progressive fibrosing interstitial lung diseases (PF-ILD) have poor prognosis and survival, and their pathogenesis is not well understood[1]. Mechanistically, lung fibrosis is thought to result from distorted wound-healing following tissue insults and inflammation, leading to scar formation by excess deposition of extracellular matrix proteins and destruction of lung architecture[2]. The fibrotic process is complex, and CD4+ T cells are likely involved by their production of a wide range of cytokines and growth factors that promote fibroblast proliferation and differentiation, collagen production, and stimulate production of pro-fibrotic mediators by tissue macrophages[3]. However, CD4+ T cells in PF-ILD are poorly characterized. To this end, we performed a detailed analysis of phenotype, cytokine production and clonality of T cells from the lungs [bronchoalveolar lavage (BAL)] of PF-ILD patients. We found that BAL from PF-ILD lungs contained high numbers of clonally expanded CD4+ T cells that produced an unusual combination of interferon (IFN) and pro-fibrotic interleukin (IL)-13. Such cells were not found in patient blood or in control BAL samples.
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Fretheim, Håvard Halland; Halse, Anne-Kristine; Seip, Marit; Bitter, Helle; Wallenius, Marianne & Garen, Torhild Oddveig
[Show all 11 contributors for this article]
(2020).
Multidimensional tracking of phenotypes and organ involvement in a complete nationwide systemic sclerosis cohort.
Rheumatology.
ISSN 1462-0324.
59(10),
p. 2920–2929.
doi:
10.1093/rheumatology/keaa026.
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Objective. SSc is a severe, heterogeneous multi-organ disease where population-based estimates on phenotypic
spectrum, overall disease burden and societal impact are largely missing. Here the objective was to provide the
first-ever complete national-level data on phenotype and major organ afflictions in SSc.
Methods. A stepwise strategy was applied to find and characterize every SSc patient resident in Norway from
2000 to 2012. First we identified every case in the country registered with an International Classification of
Diseases, Tenth Revision code for SSc (M34). Next we manually reviewed all cases coded as M34 to determine
whether they met the 1980 ACR and/or 2013 ACR/EULAR classification criteria for SSc and could be included
in the Norwegian SSc cohort (Nor-SSc). Finally, all disease features from SSc onset to study end were
reviewed.
Results. The Nor-SSc cohort included 815 SSc patients. The mean age at diagnosis was 53 years, with 84%
females and 77% limited cutaneous SSc. The estimated incidence increased from 4 per million in 2000 to 13 per
million in 2012. We identified high cumulative frequencies of internal organ involvement, coexistence of multiple
organ afflictions across disease subsets and autoantibody status and stable frequencies of pulmonary arterial
hypertension across haemodynamic definitions, but indications of referral-related differences in pulmonary hypertension detection rates across the study area.
Conclusion. This nationwide cohort study provides new, unbiased evidence for a high disease burden in SSc
patients of Caucas
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Fretheim, Håvard Halland; Chung, Brian K.; Didriksen, Henriette; Bækkevold, Espen Sønderaal; Midtvedt, Øyvind & Brunborg, Cathrine
[Show all 18 contributors for this article]
(2020).
Fecal Microbiota Transplantation in Systemic Sclerosis: A Double-Blind, Placebo-Controlled Randomized Pilot Trial.
PLOS ONE.
15:e0232739(5),
p. 1–14.
doi:
10.1371/journal.pone.0232739.
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Objectives Systemic sclerosis (SSc) is an auto-immune, multi organ disease marked by severe gastrointestinal (GI) involvement and gut dysbiosis. Here, we aimed to determine the safety and efficacy of fecal microbiota transplantation (FMT) using commercially-available anaerobic cultivated human intestinal microbiota (ACHIM) in SSc. Methods Ten patients with SSc were randomized to ACHIM (n = 5) or placebo (n = 5) in a double-blind, placebo-controlled 16-week pilot. All patients had mild to severe upper and lower GI symptoms including diarrhea, distention/bloating and/or fecal incontinence at baseline. Gastroduodenoscopy transfer of ACHIM or placebo was performed at weeks 0 and 2. Primary endpoints were safety and clinical efficacy on GI symptoms assessed at weeks 4 and 16. Secondary endpoints included changes in relative abundance of total, immunoglobulin (Ig) A- and IgM-coated fecal bacteria measured by 16s rRNA sequencing. Results ACHIM side effects were mild and transient. Two placebo controls experienced procedure-related serious adverse events; one developed laryngospasms at week 0 gastroduodenoscopy necessitating study exclusion whilst one encountered duodenal perforation during gastroduodenoscopy at the last study visit (week 16). Decreased bloating, diarrhea and/or fecal incontinence was observed in four of five patients in the FMT group (week 4 or/and 16) and in two of four in the placebo group (week 4 or 16). Relative abundance, richness and diversity of total and IgA-coated and IgM-coated bacteria fluctuated more after FMT, than after placebo. Conclusions FMT of commercially-available ACHIM is associated with gastroduodenoscopy complications but reduces lower GI symptoms by possibly altering the gut microbiota in patients with SSc.
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Holme, Sigrun Skaar; Moen, Jon Magnus; Kilian, Karin Renate; Eggesbø, Heidi Beate & Molberg, Øyvind
(2020).
Impact of Paranasal Sinus Surgery in Granulomatosis With Polyangiitis: A Longitudinal Computed Tomography Study.
The Laryngoscope.
ISSN 0023-852X.
130(8),
p. E460–E468.
doi:
10.1002/lary.28639.
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Objectives/Hypothesis Severe chronic rhinosinusitis (CRS) in patients with granulomatosis with polyangiitis (GPA) failing medical therapies can be treated with paranasal sinus surgery. Whether this surgery protects from progressive sinonasal damage remains unknown. Here, we aimed to analyze time‐dependent relations between sinus surgeries and computed tomography (CT) imaging features in the CRS of GPA. Study Design Longitudinal observational study. Methods We assessed CRS features including bone thickening by global osteitis scoring scale, bone erosions, and mucosal thickening by Lund‐Mackay scores in serial paranasal sinus CT scans (742 CT scans in total) from a cohort of 127 well‐characterized GPA patients. Data on sinonasal surgical procedures were from a mandatory national registry and from chart review. We defined the time from baseline CT to last CT as the study observation period in each patient. Datasets were analyzed by linear mixed models. Results We found that 23/127 cohort patients had one or more paranasal sinus surgical procedures, and 96% of these (22/23) had osteitis by CT after surgery. In patients with nasal surgery alone or no surgery, we identified osteitis in 7/11 (64%) and 45/93 (48%), respectively. During the observation period of a median of 5 years, 38 patients had progression of their sinus osteitis, with the highest annual osteitis progression rates observed around the time of surgery. Conclusions In this cohort, paranasal sinus surgery was associated with prevalence, severity, and progression rate of sinus osteitis, indicating that sinus surgery does not reduce the bone damage development in the CRS of GPA.
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Hoffmann-Vold, Anna-Maria & Molberg, Øyvind
(2020).
Detection, screening, and classification of interstitial lung disease in patients with systemic sclerosis.
Current Opinion in Rheumatology.
ISSN 1040-8711.
32(6),
p. 497–504.
doi:
10.1097/BOR.0000000000000741.
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Hoffmann-Vold, Anna-Maria; Fretheim, Håvard Halland; Halse, Anne-Kristine; Seip, Marit; Bitter, Helle & Wallenius, Marianne
[Show all 13 contributors for this article]
(2019).
Tracking impact of interstitial lung disease in systemic sclerosis in a complete nationwide cohort.
American Journal of Respiratory and Critical Care Medicine.
ISSN 1073-449X.
200(10),
p. 1258–1266.
doi:
10.1164/rccm.201903-0486OC.
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Rationale: Interstitial lung disease (ILD) represents a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on its overall impact, limiting opportunities for screening and management strategies.
Objectives: Evaluate impact of ILD in a unique, nationwide, population-based SSc cohort.
Methods: ILD was assessed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SSc resident in the country from 2000 to 2012. Lung high-resolution computed tomography (HRCT) scans were available for fibrosis quantification at baseline (n = 650, 80%) and follow-up. Pulmonary function tests were assessed at baseline (n = 703, 86%) and follow-up. Vital status and standardized mortality ratios (SMRs) were estimated at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched control subjects. Cumulative survival rates were computed.
Measurements and Main Results: At baseline, 50% of the subjects with SSc (n = 324) had ILD by HRCT and 46% displayed pulmonary function declines consistent with ILD progression. Mortality correlated with extent of lung fibrosis as SMR increased from 2.2 with no fibrosis to 8.0 with greater than 25% fibrosis. SMR was inversely related to baseline FVC% and increased at all FVC levels below 100%. In patients with normal-range baseline FVC (80–100%), the 5- and 10-year survival rates correlated with presence or absence of lung fibrosis, being 83% and 80%, respectively, with no fibrosis and 69% and 56%, respectively, with lung fibrosis (P = 0.03).
Conclusions: The mere presence of ILD at baseline appears to affect outcome in SSc, suggesting that all patients with SSc should undergo a baseline pulmonary function test and lung HRCT screening to diagnose ILD early and tailor further management.
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Tennøe, Anders H; Murbraech, Klaus; Andreassen, Johanna; Fretheim, Håvard Halland; Midtvedt, Øyvind & Garen, Torhild Oddveig
[Show all 12 contributors for this article]
(2019).
Systolic Dysfunction in Systemic Sclerosis: Prevalence and Prognostic Implications.
ACR Open Rheumatology.
1(4),
p. 258–266.
doi:
10.1002/acr2.1037.
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Objective Primary cardiac involvement is presumed to account for a substantial part of disease‐related mortality in systemic sclerosis (SSc). Still, there are knowledge gaps on the evolution and total burden of systolic dysfunction in SSc. Here we evaluated prospective left ventricular (LV) and right ventricular (RV) systolic function in an unselected SSc cohort and assessed the burden of systolic dysfunction on mortality. Methods From the Oslo University Hospital cohort, 277 SSc patients were included from 2003‐2016 and compared with healthy controls. Serial echocardiographies were reevaluated in order to detect change in systolic function. Right heart catheterization was performed on patients suspected of pulmonary hypertension. Descriptive and regression analyses were conducted. Results At baseline, LV systolic dysfunction by ejection fraction less than 50%, or a global longitudinal strain greater than −17.0%, was found in 12% and 24%, respectively. RV systolic dysfunction measured by tricuspid annular plane systolic excursion (TAPSE) less than 17 mm was evident in 10%. Follow‐up echocardiography was performed after a median of 3.3 years (interquartile range [IQR] 1.5‐5.6). At follow‐up, LV systolic function remained stable, whereas RV function evaluated by TAPSE deteriorated (mean 23.1 to 21.7 mm, P = 0.005) equaling a 15% prevalence of RV systolic dysfunction. RV systolic function predicted mortality in multivariable models (hazard ratio 0.41, 95% confidence interval [CI] 0.19‐0.90, P value 0.027), whereas LV systolic function lost predictive significance when adjusted for TAPSE. Conclusion In this unselected and prospective study, systolic dysfunction of the LV and RV was a frequent complication of SSc. LV systolic function remained stable across the observation period, whereas RV function deteriorated and predicted mortality.
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Holme, Sigrun Skaar; Moen, Jon Magnus; Kilian, Karin Renate; Haukeland, Hilde; Molberg, Øyvind & Eggesbø, Heidi Beate
(2019).
Development of CT-based methods for
longitudinal analyses of paranasal sinus
osteitis in granulomatosis with polyangiitis.
BMC Medical Imaging.
19(1),
p. 1–11.
doi:
10.1186/s12880-019-0315-7.
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Background Even though progressive rhinosinusitis with osteitis is a major clinical problem in granulomatosis with polyangiitis (GPA), there are no studies on how GPA-related osteitis develops over time, and no quantitative methods for longitudinal assessment. Here, we aimed to identify simple and robust CT-based methods for capture and quantification of time-dependent changes in GPA-related paranasal sinus osteitis and compare performance of the methods under study in a largely unselected GPA cohort. Methods GPA patients (n = 121) with ≥3 paranasal CT scans obtained ≥12 months apart and control patients not having GPA or rhinosinusitis (n = 15) were analysed by: (i) Global osteitis scoring scale (GOSS), originally developed for chronic rhinosinusitis; (ii) Paranasal sinus volume by manual segmentation; (iii) Mean maxillary and sphenoid diameter normalised to landmark distances (i.e. diameter ratio measurement, DRM). Results Time-dependent changes in GPA-related osteitis were equally well measured by the simple DRM and the labour-intensive volume method while GOSS missed ongoing changes in cases with extensive osteitis. GOSS at last CT combined with DRM identified three distinct patient groups: (i) The no osteitis group, who had no osteitis and no change in DRM from baseline CT to last CT (45/121 GPA patients and 15/15 disease controls); (ii) Stable osteitis group, with presence of osteitis, but no change in DRM across time (31 GPA); (iii) Progressive osteitis, defined by declining DRM (45 GPA). Conclusions We suggest DRM and GOSS as complementary methods for capturing, classifying and quantifying time-dependent changes in GPA-related osteitis.
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Rothwell, Simon; Chinoy, Hector; Lamb, Janine A.; Miller, Frederick W.; Rider, Lisa G. & Wedderburn, Lucy R.
[Show all 33 contributors for this article]
(2019).
Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.
Annals of the Rheumatic Diseases.
ISSN 0003-4967.
78(7),
p. 996–1002.
doi:
10.1136/annrheumdis-2019-215046.
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Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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Moe, Sigrid E Reppe; Molberg, Øyvind; Strøm, Erik Heyerdahl & Lerang, Karoline
(2019).
Assessing the relative impact of lupus nephritis on mortality in a population-based systemic lupus erythematosus cohort.
Lupus.
ISSN 0961-2033.
doi:
10.1177/0961203319847275.
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Objective There is limited knowledge on the relative impact of lupus nephritis (LN) on morbidity and mortality in population-based systemic lupus erythematous (SLE) cohorts. Here, the primary aim was to compare mortality rates between patients with and without LN in a population-based SLE cohort. Methods The study cohort included all SLE patients resident in the city of Oslo during 1999–2008. Follow-up time was median 14 (0–15) years. Presence of LN was defined according to the 1987 American College of Rheumatology classification criteria for SLE. LN class was determined by renal biopsy. Data on kidney function, including presence of end-stage renal disease (ESRD), were obtained from patient charts. Standardized mortality ratios (SMRs) were estimated by comparing deaths in the SLE cohort with age- and gender-matched population controls. Results We found that 98/325 SLE patients (30%) developed LN, 92% of whom had occurrence within the first five years from disease onset. Incidence rate of ESRD was 2.3 per 1000 patient-years. A total of 56 deaths occurred during the study period, corresponding to an overall SMR in the SLE cohort of 2.1 (95% confidence interval (CI) 1.2–3.4). Estimated SMR for LN patients was 3.8 (95% CI 2.1–6.2), and for SLE patients without LN it was 1.7 (95% CI 0.9–2.7). Conclusion In this population-based SLE cohort, we found that LN was associated with increased morbidity and mortality, whereas SLE patients who did not develop LN had good overall prognoses regarding survival.
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Elhai, Muriel; Hoffmann-Vold, Anna-Maria; Avouac, Jérôme; Pezet, Sonia; Cauvet, Anne & Leblond, Agnés
[Show all 11 contributors for this article]
(2019).
Performance of Candidate Serum Biomarkers for Systemic Sclerosis?Associated Interstitial Lung Disease.
Arthritis & Rheumatology.
ISSN 2326-5191.
71(6),
p. 972–982.
doi:
10.1002/art.40815.
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Objective Interstitial lung disease (ILD ) in systemic sclerosis (SS c) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SS c‐associated ILD . Methods Serum samples from a combined cohort of SS c patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme‐linked immunosorbent assay for concentrations of lung epithelial–derived surfactant protein D (SP ‐D), Krebs von den Lungen 6 glycoprotein (KL ‐6), CCL 18, and OX 40 ligand (OX 40L). Lung fibrosis was measured by high‐resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow‐up 3.2 ± 4.4 years) were investigated. Results In SS c patients at baseline, serum levels of KL ‐6 correlated with the forced vital capacity (FVC ) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL ‐6 and SP ‐D, but not CCL 18 and OX 40L, were associated with lung fibrosis (odds ratio [OR ] 2.41, 95% confidence interval [95% CI ] 1.43–4.07 [P = 0.001] and OR 3.15, 95% CI 1.81–5.48 [P < 0.001], respectively). In SS c patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL 18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR ] 2.90, 95% CI 1.25–6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02–13.52; P = 0.048). Matrix‐based logistic regression models for the diagnosis and prognosis of SS c‐associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP ‐D (for diagnosis) and serum levels of CCL 18 (for progression of disease). Conclusion These results show that SP ‐D is a relevant diagnostic biomarker for SS c‐associated ILD , whereas KL ‐6 could be used to assess the severity of lung fibrosis. CCL 18 appears to be a potential predictive marker for progression of ILD in SS c.
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Christophersen, Asbjørn; Lund, Eivind Gard; Snir, Omri; Solà, Elsa; Kanduri, Srinivasa Kalyana Chakravarthi & Dahal-Koirala, Shiva
[Show all 15 contributors for this article]
(2019).
Distinct phenotype of CD4+ T cells driving celiac disease identified in multiple autoimmune conditions.
Nature Medicine.
ISSN 1078-8956.
25(5),
p. 734–737.
doi:
10.1038/s41591-019-0403-9.
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Combining HLA-DQ–gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.
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Guderud, Kari; Mæhlen, Marthe Thoresen; Namløs, Gry Beate; Viken, Marte K; Kulle, Bettina & Molberg, Øyvind
[Show all 8 contributors for this article]
(2018).
Lack of association among peptidyl arginine deiminase type 4 autoantibodies, PADI4 polymorphisms, and clinical characteristics in rheumatoid arthritis.
Journal of Rheumatology.
ISSN 0315-162X.
45(9),
p. 1211–1219.
doi:
10.3899/jrheum.170769.
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Objective.We aimed to jointly investigate the role of antipeptidyl arginine deiminase type 4 antibodies
(anti-PAD4) and polymorphisms in the PADI4 gene together with clinical variables in rheumatoid
arthritis (RA).
Methods. Serum IgG autoantibodies to human recombinant PAD4 were identified by DELFIA
technique in 745 patients with RA (366 available from previous studies). Genotyping of PADI4 was
performed using TaqMan assays in 945 patients and 1118 controls. Clinical data, anticitrullinated
protein antibodies (ACPA) status, shared epitope status, and a combined genetic risk score were also
available.
Results. Anti-PAD4 antibodies were detected in 193 (26%) of 745 patients with RA; 149 (77%) of
these were also ACPA-positive. No association was observed between anti-PAD4 status and clinical
characteristics, PADI4 polymorphisms, or genetic risk scores after stratification for ACPA status.
Conclusion. Taken together, the results from these combined serological, genetic, and clinical analyses
suggest that anti-PAD4 appears to be a bystander autoantibody with no current clinical utility in RA.
(First Release June 1 2018; J Rheumatol 2018;45:1211–19; doi:10.3899/jrheum.170769)
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Hoffmann-Vold, Anna-Maria; Weigt, Stefan; Palchevskiy, Vyacheslav; Volkmann, Elizabeth R.; Saggar, Rajan & Li, Ning
[Show all 18 contributors for this article]
(2018).
Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis.
PLOS ONE.
13(11),
p. 1–15.
doi:
10.1371/journal.pone.0206545.
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Background: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. Methods: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. Results: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. Conclusion: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.
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Risum, Kristine; Edvardsen, Elisabeth; Godang, Kristin; Selvaag, Anne Marit G; Hansen, Bjørge Hermann & Molberg, Øyvind
[Show all 10 contributors for this article]
(2018).
Physical Fitness in Patients With Oligoarticular and Polyarticular Juvenile Idiopathic arthritis diagnosed in the era of biologics: A controlled cross-sectional study.
Arthritis care & research.
ISSN 2151-464X.
71(12),
p. 1611–1620.
doi:
10.1002/acr.23818.
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González-Gay, Miguel A.; Montecucco, Carlomaurizio; Selva-O'Callaghan, Albert; Trallero-Araguas, Ernesto; Molberg, Øyvind & Andersson, Anna Helena
[Show all 79 contributors for this article]
(2018).
Timing of onset affects arthritis presentation pattern in antisynthetase syndrome.
Clinical and Experimental Rheumatology.
ISSN 0392-856X.
36(1),
p. 44–49.
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Risum, Kristine; Hansen, Bjørge Hermann; Selvaag, Anne Marit G; Molberg, Øyvind; Dagfinrud, Hanne & Sanner, Helga
(2018).
Physical activity in patients with oligo- and polyarticular juvenile idiopathic arthritis diagnosed in the era of biologics: A controlled cross-sectional study.
Pediatric Rheumatology.
16(64).
doi:
10.1186/s12969-018-0281-6.
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Background: Knowledge about objectively measured levels of physical activity (PA) and PA participation (included facilitators and barriers for PA) in patients with juvenile idiopathic arthritis (JIA) diagnosed in the era of biologics is limited. We aimed to compare objectively measured PA in patients with oligo- and polyarticular JIA diagnosed in the biologic era with controls and to examine associations between PA and disease variables; furthermore, to explore participation in PA, physical education (PE) and facilitators and barriers for PA participation in patients and controls. Methods: The study cohort included 60 patients (30 persistent oligo JIA/30 poly-articular disease) and 60 age- and sex-matched controls. Age range was 10–16 years and 83% were female. PA was measured with accelerometry for seven consecutive days. Disease activity, current treatment, disease duration, functional ability, pain and fatigue were assessed. Structured interviews were applied to explore participation in PA and PE, and PA facilitators and barriers. Results: Patients spent less time in daily vigorous PA than controls, (mean(SE) 21(2) min vs. 26(2) min, p = 0.02), while counts per minute (cpm), steps daily, sedentary time and light and moderate PA did not differ. No differences were found between JIA subgroups. The use of biologic medication was associated with higher cpm and lower sedentary time. Most patients and controls participated in organized or unorganized PA and PE, and enjoyment was the most reported facilitator for PA participation. More patients than controls reported pain as a PA barrier. Conclusion: The PA levels and participation in patients with oligo- and polyarticular JIA are mostly comparable to controls, but patients still need to be encouraged to increase vigorous PA. Enjoyment is the most important facilitator for PA participation in patients with JIA.
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Tennøe, Anders; Murbræch, Klaus; Andreassen, Johanna; Fretheim, Håvard Halland; Garen, Torhild Oddveig & Gude, Einar
[Show all 10 contributors for this article]
(2018).
Left ventricular diastolic dysfunction predicts mortality in patients with systemic sclerosis.
Journal of the American College of Cardiology.
ISSN 0735-1097.
72(15),
p. 1804–1813.
doi:
10.1016/j.jacc.2018.07.068.
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Background Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality. Objectives The purpose of this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality. Methods SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted. Results Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84). Conclusions DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.
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Oma, Ingvild; Olstad, Ole Kristoffer; Andersen, Jacqueline Kirsti; Lyberg, Torstein; Molberg, Øyvind & Fostad, Ida
[Show all 13 contributors for this article]
(2018).
Differential expression of Vitamin D associated genes in the aorta of coronary artery disease patients with and without rheumatoid arthritis.
PLOS ONE.
13:e0202346(8),
p. 1–13.
doi:
10.1371/journal.pone.0202346.
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Background Vitamin D has an important role in the immune system, and has been linked to rheumatoid arthritis (RA) and coronary artery disease (CAD). The exact mechanisms by which vitamin D is involved in these processes are still unclear. Therefore, we wanted to search for differences in expression of genes involved in the vitamin D receptor (VDR) activation pathway and genes that are known to alter upon vitamin D stimulation, in the aortic adventitia of CAD patients with and without RA. Methods Affymetrix microarray was used to determine gene expression profile in surgical specimens from the adventitia of the ascending aorta of CAD patients with RA (n = 8) and without RA (n = 8) from the Feiring Heart Biopsy Study. Results We identified three vitamin D associated genes that were differentially expressed between RA and non-RA patients: Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) (FC = 1.47; p = 0.006), Nuclear Receptor Co-repressor 1 (NCOR1) (FC = 1,21; p = 0.005) and paraoxonases 2 (PON2) (FC = -1.37; p = 0.01). High expression of GADD45A in RA tissues was confirmed by real-time qRT-PCR. GADD45A expression correlated with plasma levels of 1,25(OH)2D3 (rs = 0.69; p = 0.003). Conclusions Microarray analyses revealed higher expression of GADD45A and NCOR1; and lower expression of PON2 in the aortic adventitia of RA than non-RA patients. Further studies are needed to elucidate if and how GADD45A, NCOR1 and PON2 are involved in the development of accelerated atherosclerosis in RA. In theory, some of these factors might have proatherogenic effects whereas others might reflect an underlying vascular pathology promoting atherogenesis (such as vascular stress).
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Risum, Kristine; Stamnæs, Jorunn; Alexanderson, Helene; Molberg, Øyvind & Sanner, Helga
(2026).
Altered acute inflammatory response to maximal treadmill exercise in children and adolescents with juvenile idiopathic arthritis.
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Molberg, Øyvind
(2026).
Nytt forskningssenter for autoimmune sykdommer | Norsk Revmatikerforbund.
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I juni ble det nye K. G. Jebsen-senteret for spesifikk autoimmun terapi ved Rikshospitalet offisielt åpnet.
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Kvaal, Julie Nybakk & Molberg, Øyvind
(2026).
Kvinne frisk av alvorlig autoimmun sykdom: – Kan endre måten vi behandler slike sykdommer på.
[Journal].
forskning.no.
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Kan en ny kreftbehandling hjelpe pasienter med autoimmune sykdommer som leddgikt?
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Daniloff, Kathrine; Kristiansen, Milli Malene Berg & Molberg, Øyvind
(2026).
CAR T-cellebehandling ved autoimmune sykdommer.
doi:
https:/www.youtube.com/watch?v=Pzd1VNTQqf8&t=18s.
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en innføring i CAR T-cellebehandling – en ny behandlingsform som kan få stor betydning for enkelte pasienter med alvorlige autoimmune sykdommer.
Molberg arbeider ved Avdeling for revmatologi ved Oslo universitetssykehus og er professor ved Universitetet i Oslo. Han forsker på systemiske autoimmune revmatiske sykdommer og er involvert i kliniske studier av CAR T-cellebehandling i Norge.
CAR T-cellebehandling ble opprinnelig utviklet for behandling av enkelte former for blodkreft. Behandlingen går ut på at pasientens egne T-celler tas ut og endres genetisk, slik at de kan gjenkjenne og fjerne bestemte celler. Ved autoimmune sykdommer forsøker man å fjerne B-celler som er med på å drive sykdommen.
Autoimmune sykdommer oppstår når immunsystemet angriper kroppens eget vev. Mange får god hjelp av dagens behandling, men noen har alvorlig sykdom som ikke lar seg kontrollere, selv etter behandling med flere ulike immundempende legemidler.
For disse pasientene kan sykdommen gi alvorlig og i noen tilfeller livstruende skade på blant annet nyrer, lunger, hud og muskler. Behandlingen kan samtidig være krevende og innebære bruk av mange medisiner over lang tid.
Tidlige studier av CAR T-cellebehandling har vist svært lovende resultater, særlig hos pasienter med alvorlig lupus, men også ved systemisk sklerose og myositt. Noen pasienter har kommet i langvarig remisjon og kunnet slutte med annen behandling.
Resultatene har ført til stor internasjonal forskningsaktivitet, men behandlingen er fortsatt under utprøving ved autoimmune sykdommer.
Molberg forklarer hvilken rolle B-cellene har i immunforsvaret, og hvorfor de kan bidra til å opprettholde autoimmune sykdommer.
Han viser hvordan CAR T-cellebehandlingen gjennomføres, hvilke pasienter som kan være aktuelle, og hvilke resultater som hittil er rapportert.
Han omtaler også risikoen for bivirkninger, blant annet infeksjoner og midlertidig svekkelse av immunforsvaret.
Molberg avslutter med å fortelle hvor forskningen står i Norge. Norske fagmiljøer deltar i internasjonale studier, har gjennomført de første behandlingene og arbeider med å etablere lokal produksjon av CAR T-celler i Oslo.
Målgruppen for webinaret er først og fremst helsepersonell som ønsker en oppdatert innføring i CAR T-cellebehandling ved autoimmune sykdommer.
Webinaret kan også være relevant for pasienter, pårørende og andre som ønsker grundig kunnskap om utviklingen på feltet. Enkelte deler er medisinskfaglige, men Molberg forklarer behandlingsprinsippene trinn for trinn.
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Hetlevik, Siri Opsahl; Lilleby, Vibke; Pesonen, Maiju; Nordal, Ellen Berit; Rygg, Marite & Austad, Cathrine
[Show all 17 contributors for this article]
(2026).
Moving towards optimized treatment for children and adolescents with juvenile idiopathic arthritis in sustained remission randomized to continue stable treatment, methotrexate withdrawal or tumor necrosis factor inhibitor withdrawal: study protocol for the Norwegian multi-center MOVE-JIA trial.
doi:
10.1186/s13063-026-09539-0.
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Bøyesen, Pernille; Aga, Anna-Birgitte; Lilleby, Vibke; Pesonen, Maiju; Rygg, Marite & Nordal, Ellen Berit
[Show all 17 contributors for this article]
(2025).
O09 Long-term treatment efficacy of intra-articular triamcinolone hexacetonide injections in juvenile idiopathic arthritis patients starting tumor necrosis factor inhibitor therapy: 48-week results from a randomized, phase 4 trial - the myjia trial.
Pediatric Rheumatology.
23(2).
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Hov, Johannes Espolin Roksund; Molberg, Øyvind & Karlsen, Tom Hemming
(2024).
Tubulin beta 5 is not the target of antineutrophil antibodies in primary sclerosing cholangitis.
Clinical and Experimental Immunology.
ISSN 0009-9104.
218(1),
p. 75–77.
doi:
10.1093/cei/uxae053.
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Vikse, Jens; Bader, Lucius; Goll, Guro Løvik; Molberg, Øyvind & Haavardsholm, Espen A.
(2024).
Immunsupprimerende behandling.
In Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Ed.),
Revmatologi.
Universitetsforlaget.
ISSN 9788215068589.
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Vikse, Jens; Fevang, Bjørg Tilde Svanes; Haugeberg, Glenn; Bitter, Helle; Haavardsholm, Espen A. & Molberg, Øyvind
(2024).
Revmatologi: en oversikt.
In Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Ed.),
Revmatologi.
Universitetsforlaget.
ISSN 9788215068589.
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Vikse, Jens; Christophersen, Asbjørn; Goll, Guro Løvik & Molberg, Øyvind
(2024).
Immunologi: en oversikt.
In Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Ed.),
Revmatologi.
Universitetsforlaget.
ISSN 9788215068589.
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Hoffmann-Vold, Anna-Maria; Fretheim, Håvard Halland; Didriksen, Henriette & Molberg, Øyvind
(2020).
The potential of fecal microbiota transplantation in systemic sclerosis.
Expert Review of Clinical Immunology.
ISSN 1744-666X.
VOL. 16,(NO. 2,),
p. 117–118.
doi:
10.1080/1744666X.2019.1707665.
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Risum, Kristine; Hansen, Bjørge Hermann; Selvaag, Anne Marit G; Molberg, Øyvind; Dagfinrud, Hanne & Sanner, Helga
(2018).
Fysisk aktivitet hos pasienter med juvenil idiopatisk artritt- en kontrollert tverrsnittsstudie.
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Risum, Kristine; Selvaag, Anne Marit; Molberg, Øyvind; Dagfinrud, Hanne & Sanner, Helga
(2018).
Estimated peak oxygen uptake and submaximal parameters from a submaximal treadmill test are comparable between patients with oligo- and polyarticular juvenile idiopathic arthritis diagnosed in the era of biologics and controls- a controlled cross-sectional study.
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Risum, Kristine; Edvardsen, Elisabeth; Selvaag, Anne Marit; Molberg, Øyvind; Dagfinrud, Hanne & Sanner, Helga
(2018).
Kardiorspiratorisk form hos pasienter med juvenile idiopatisk artritt- en kontrollert tverrsnittsstudie.
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Risum, Kristine; Edvardsen, Elisabeth; Selvaag, Anne Marit; Molberg, Øyvind; Dagfinrud, Hanne & Sanner, Helga
(2018).
Criterion validity and reliability of a submaximal treadmill test in juvenile idiopathic arthritis patients.
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Published
Apr. 13, 2011 2:54 PM
- Last modified
May 27, 2011 4:08 PM
